Autoantibody targeting therapies in post COVID syndrome and myalgic encephalomyelitis/chronic fatigue syndrome, 2025, Wohlrab et al

[Nightsong]

Introduction:

Following the shift of SARS-CoV-2 from pandemic to endemic, post COVID syndrome (PCS) joins the list of already known post-acute infection syndromes (PAIS) and its most severe manifestation, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The exact pathomechanism of PCS has not yet been fully understood.

Immune dysregulation with persistent inflammation, microvascular injury with endothelial dysfunction, autonomic nervous system dysfunction, mitochondrial dysfunction, gut microbiome dysbiosis and persistence of SARS-CoV-2 virus or SARS-CoV-2 viral particles have been proposed [1].

Autoimmunity could be a linking element across various mechanisms and there is indeed mounting evidence that autoantibodies (AAbs) in particular play a role in a subset of PCS and ME/CFS.

In ME/CFS there are now numerous studies showing elevated levels and altered functions of G-protein coupled receptor autoantibodies (GPCR AAbs) and their correlation with severity of key symptoms [2].

First trials with AAb-targeting therapies show promising though mixed results. These include studies directly targeting AAbs by removal with immunoadsorption or their enhanced degradation with efgartigimod or neutralization with BC007 (rovunaptabin). Further B cell depletion with rituximab or plasma cell depletion with daratumumab has yielded some positive but inconsistent results.

https://www.tandfonline.com/doi/full/10.1080/14712598.2025.2492774

 

[Andy]

An editorial whose author list includes Scheibenbogen.

 

[forestglip]

There's a nice table summarizing the state of autoantibody targeting therapies:

 

[Utsikt]

There's a nice table summarizing the state of autoantibody targeting therapies:

View attachment 25806

Is the Dara preliminary positive results from Fluge and Mella?

 

[Jonathan Edwards]

I might just throw in that the hint of benefit with all these antibody depleting approaches might be real and masked by suboptimal drug efficacy. (Although it might be a mirage.) But it might not be targeting autoantibody. The benefit might come from depleting perfectly normal antibody!

I will explain more in due course.

 

[Turtle]

Are (auto)antibodies always bad things?

 

[Jonathan Edwards]

Are (auto)antibodies always bad things?

Probably. I cannot think of a known example of a useful autoantibody at present and it is hard to see what the biological advantage would be of having one.

There are things called natural autoantibodies of low affinity that might just do a useful job. The main one being rheumatoid factor, which in theory can amplify the effect of antibodies to foreign antigens. But more likely these low affinity antibodies with auto reactivity are just noise-type cross-reactive binding I think.

Jo Cambridge might correct me here.

 

[EndME]

Seems like there is wishful reporting and the omission of negative trial results (for instance
Immune adsorption for the treatment of fatigue-dominant long-/post-COVID syndrome—a case series).

Seems a bit odd to mention limitations for trials with negative results but not mention those when they apply to trials with positive results.

The only trials that were somewhat large and placebo-controlled Rituximab, Efgartigimod and BC007 showed no difference in the groups.

 

[Jonathan Edwards]

Yes, the presentation is a little optimistic. The phase II rituximab trial did to give 'promising results'. The primary end point was not met. The reason for going to phase III was that a different endpoint showed a statistically significant difference and in hindsight this probably should have been chosen as primary end point. However, the progression to phase III was not so much following a positive result as a courageous attempt to make sure that a positive result had not been missed through poor choice of primary outcome at phase II.

In retrospect, looking at the time profile for individual cases, the apparently positive result at 6 months in phase II looks very much like a chance random finding amongst very noisy data.

 

[V.R.T.]

I am really interested in whether the efgartigimod trials failed because they used a very restrictive POTS measurement. A lot of participants reported a benefit to PEM and POTS afterwards and were trying to get the raw data.

BC007 i am more skeptical about because of the insane hype, but there were quite a lot of significant improvement stories floating around on social media...the Erlangen data was thoroughly unimpressive though.

 

[sneyz]

Is the Dara preliminary positive results from Fluge and Mella?

Yes!

From the paper: «Daratumumab is currently being tested in a clinical pilot open study of moderate to severe ME/CFS in Norway (EudraCT number: 2022-000281-18).»

 

[Jaybee00]

I might just throw in that the hint of benefit with all these antibody depleting approaches might be real and masked by suboptimal drug efficacy. (Although it might be a mirage.) But it might not be targeting autoantibody. The benefit might come from depleting perfectly normal antibody!

Earlier I asked you about this and you said it wasn’t important. IGG measures total antibodies, correct?

I wouldn't expect total IgG levels to be terribly relevant to any response.
And we are expecting a fall over that time frame so not sure it needs to link to symptoms.
The improvement in symptoms is substantial but then we don't have any controls and we saw things like that with rituximab.

Initial levels of IgG are unlikely to mean anything. I don't see enough data to generalise ?

From both the Fluge cyclo and daratumumab studies there is no response in patients who didn’t lower their IGG levels.

 

[Jaybee00]

Here is your similar comment regarding IGG for the cyclo study

I don't think the differences will tell us anything specific. Immunoglobulin levels in normal people vary greatly, and apparently of no relevance to health. The IgG differences shown are well in the normal range and give us no functional clues to anything.

Happy that you are coming over to the dark side now!

 

[Kitty]

IGG measures total antibodies, correct?

Or is it just levels of IgG?

(I know nowt about it, to be fair.)

 

[Jonathan Edwards]

Earlier I asked you about this and you said it wasn’t important. IGG measures total antibodies, correct?

Ah but this is something different. A completely new thought.

From both the Fluge cyclo and daratumumab studies there is no response in patients who didn’t lower their IGG levels.

Which would be very interesting if it holds up.

 

[Jonathan Edwards]

Happy that you are coming over to the dark side now!

It's more of 'Third Way' perhaps.

 

[Jonathan Edwards]

Or is it just levels of IgG?

Yes it's just IgG. But whichever current theory we are talking about IgG is likely to be what matters. Although it is conceivable that other isotypes are relevant.

IgM tends to fall just with rituximab so maybe that is not where the money is.

 

[Utsikt]

Yes it's just IgG. But whichever current theory we are talking about IgG is likely to be what matters. Although it is conceivable that other isotypes are relevant.

IgM tends to fall just with rituximab so maybe that is not where the money is.

How would apheresis or other filtering interventions fit into this, if at all? Could you reasonably mechanically remove the IgG? How long would the body take to replenish the IgG?

 

[V.R.T.]

From both the Fluge cyclo and daratumumab studies there is no response in patients who didn’t lower their IGG levels.

Efgartigimod also lowers IgG I believe...

 

[Jonathan Edwards]

How would apheresis or other filtering interventions fit into this, if at all? Could you reasonably mechanically remove the IgG? How long would the body take to replenish the IgG?

You can reduce IgG levels but it is a laborious process and the more you pherese the less you get out. It has never seemed to me more than a salvage option when nothing else has worked.

I think IgG last about 100 days but it varies with antibody and in some cases may be much shorter. That probably means that IgG will recover within a month or two. That is roughly what we saw when patients on rituximab had drops in total IgG levels.